Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. Secondary mutations as mediators of resistance to targeted therapy in leukemia. Google Scholar. By submitting a comment you agree to abide by our Terms and Community Guidelines. Favorable relapse risk and OS were seen in NPM1mut with FLT3 wild-type; intermediate prognosis in FLT3-ITDmut with concurrent NPM1mut, and adverse prognosis in FLT3-ITDmut with NPM1 wild-type patients16. and P.M.; Validation, T.C., J.M.A., E.B. AML patients with FLT3-ITD mutations show an increased relapse rate, reduced disease-free survival (DFS), and decreased long-term survival, while the rate of complete remission (CR) after induction chemotherapy is not significantly affected6,7. Internet Explorer). The number, area and length of mutant peaks on capillary electrophoresis were analyzed using GeneMapper analysis software (Applied Biosystems, Foster City, CA). Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. S2) in PETHEMA centralized diagnostic laboratories as previously described33. Blood 121, 46554662 (2013). Kiyoi, H., Ohno, R., Ueda, R., Saito, H. & Naoe, T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. We currently recommend post-transplant maintenance with a FLT3i for at least 2 years (potentially indefinitely as there is limited data on the incidence of possible late relapses) in all FLT3mut AML. In particular, high (>0.5) mutant-to-wild-type (WT) allelic ratios (AR) in the FLT3-ITD gene are associated with inferior prognosis ( 6, 7 ). 383, 617629 (2020). Naval Daver, M. D. et al. The role of ASCT in patients with FLT3-ITDmut AR<0.50 with concomitant NPM1mut in the absence of concomitant high-risk features such as DNMT3A, TP53, or RUNX1 co-mutations, adverse cytogenetics, therapy-related or secondary AML, who achieve MRD negativity by high-sensitivity PCR (ideally for NPM1mut), or patients with FLT3-TKDmut is an area of ongoing debate. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. AR,allelic ratio. Addition of venetoclax to this backbone may be associated with prolonged and potentially prohibitive myelosuppression; we have not routinely added and do not at this time recommend adding venetoclax to the backbone of CLIA/FIA with FLT3i63. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Yamatani, K. et al. 19, 889903 (2018). Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. Ravandi, F. et al. Cancer Cell 1, 433443 (2002). Although activity was seen, the response rates were overall modest with this combination and the combination of HMA with midostaurin is not one that we routinely use or recommend for frontline FLT3-mutated AML47. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). F fludarabine, I idarubicin, CL cladribine, A cytarabine 1.52g/m2, HMA hypomethylating agent, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Performance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, HiDAC high-dose cytarabine, CBC complete blood count. (4) Only five patients in our cohort received treatment with midostaurin (2 in induction and 3 in consolidation treatment); therefore, we were not able to draw conclusions regarding the prognostic impact of the length of the ITD as described in previous studies29,30. Regarding ITD length, some authors have found that patients with shorter ITD lengths have more favorable outcomes11,12 or worse prognoses13, while other researchers did not find a prognostic relationship14. We evaluate these patients on a case by case basis and may consider maintenance with 45 consolidation cycles of CLIA or FAI with FLT3i followed by FLT3i+/HMA maintenance for two years vs ASCT based on donor availability, age, performance status, MRD negativity, and patient preference. Soc. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). Welch John, S. et al. Rydapt Prescribing Information. Andrew, H. et al. The landscape of mutations identified by NGS in AML patients. Google Scholar. We also performed an ROC curve analysis for OS prediction excluding those 10 patients with more than 1 ITD insertion and obtained an AUC of 0.521. Blood 111, 27762784 (2008). To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. or. The data described in the literature alongside the results that we have obtained regarding ITD mutation lead us to believe that future studies should focus on the functional characterization of the protein products of the mutated genes. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. However, the true CR/CRi rate was only 34%. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. In the treatment-naive setting, the median time to neutrophil and platelet recovery among responders was 45 and 30 days, respectively, suggesting cumulative myelosuppression is to be expected and further optimization of triplets schedules is ongoing55. Jain, P. et al. ABSTRACT. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). Hematol. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. volume11, Articlenumber:20745 (2021) Intriguingly, this was the first large study to show that the FLT3i may also benefit FLT3 wild-type patients, perhaps through multi-kinase blockade or prevention of emergent FLT3 clones at relapse28. 16, 16911699 (2015). J. Hematol. 13, 139 (2020). 90, 276281 (2015). Stone, R. M. et al. 5 96 102, C Sargas 2020 Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: The PETHEMA NGS-AML project Haematologica https://doi.org/10.3324/haematol.2020.263806, Article Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . We suggest that any investigator who wants to demonstrate the prognostic value of the ITD length applies some of the recurrent published thresholds used in this study or divides his cohort into training and validation subcohorts. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . Relapse-free survival (RFS) was calculated from the date of achieving CR/CRi until the date of relapse (death without relapse or relapse were consideredevents)8. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. Dhner, H. et al. Oran et al. Hematol. Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16) (ASH, 2020). Blood 127, 360362 (2016). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Mali, R. S. et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. 7+37 days of cytarabine and 3 days of daunorubicin. Using the same response criteria, the CRc rate was 85.4% (n=35/41) which compared favorably to 52% with gilteritinib alone in the ADMIRAL study. Conceptualization, T.C., J.M.A., E.B. You are using a browser version with limited support for CSS. CR+CRi rates between groups were compared with a chi-square test. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. The presence of FLT3-ITD mutation correlates with a high leukemic burden with increased risk of relapse and is recognized to be a driver mutation in patients with AML ( 5 ). Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. J. Natl Cancer Inst. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. Google Scholar. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. FLT3i FLT3 inhibitor, HMA hypomethylating agent, VEN venetoclax, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Perfromance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, CBC complete blood count. volume11, Articlenumber:104 (2021) Blood 128, 449452 (2016). fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. 1). Strati et al. In the absence of clinical trial options: among patients eligible for intensive chemotherapy who had a prior remission >1012 months, we would prefer a regimen incorporating intensive therapy (FLAG-Ida, CLAG-M, CLIA, MEC) in combination with a FLT3 inhibitor with an intent to achieve a rapid and hopefully deep remission and transition patients to ASCT followed by post-ASCT maintenance. Precision Medicine in Myeloid Malignancies: Hype or Hope? The sorafenib treatment arm had increased rates of adverse events, particularly diarrhea, bleeding, cardiac events, hand-foot-skin reaction, and rash but with no significant increase in the 30- or 60-day mortality between the two treatment arms. 120.000 new AML cases and over . Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia Blood Cancer J. Patients with an ITD fragment39bp or70bp had a significant reduction in OS and RFS in some of these studies, but we were unable to validate these findings11,15,16,17. In fact, every quartile increase in FLT3-ITD AR (from 0.01 to 0.20, 0.20 to 0.53, 0.53 to 0.80, 0.80 to 1.19) was associated with worsening complete remission (CR) rates, RFS, and OS, highlighting the prognostic value of AR. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. In the last 25years, advances in molecular techniques have allowed a greater understanding of the pathogenesis of AML and the subsequent development of targeted therapies and a more refined prognostic classification based on the genetic features of the disease2,3. PubMed Nature 485, 260263 (2012). Moreover, we performed an analysis of the correlation of FLT3-ITD length and insertion sites with the mutational landscape of AML, which has not been carried out thus far. Blood 93, 30743080 (1999). We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. The UKMRC group evaluated the presence of NPM1 co-mutations in young adult patients with AML. Blood 136, 1617 (2020). Two classes of activating FLT3 mutations occur in AML: (1) internal tandem duplication ( FLT3 -ITD) which occur in 20-25% of patients and (2) tyrosine kinase domain mutations ( FLT3 -TKD) which are seen in 5-10% of patients [48]. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. (5) No data regarding minimal residual disease (MRD) were available in our cohort, and MRD data could be interesting to analyze in future studies. At a median follow-up of 42 months, sorafenib demonstrated a 2-year estimated RFS of 85% and OS of 90.5% compared with 53.3% (P=0.002), and 66.2% with placebo, respectively (P=0.007). 373 1136 1152, N Daver RF Schlenk NH Russell MJ Levis 2019 Targeting FLT3 mutations in AML: Review of current knowledge and evidence Leukemia 33 299 312, Article Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Furthermore, ten patients with mutated WT1 showed a median ITD length of 77bp,and 58 patients with non-mutated WT1 showed a median ITD length of 42bp (P=0.021). FLT3 activating mutations ( FLT3mut) may involve either the juxta membrane domain [internal tandem duplication mutations ( FLT3 -ITD)] 4 or the tyrosine kinase domain ( FLT3 -TKD) 5, 6.. (2) Larger studies analyzing ITD length also found no significant results14,23,28. (C) OS according to the FLT3-ITD length and allelic ratio. Eur. Pratz, K. W. et al. The two leading types of FLT3 mutations found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and mutations in the tyrosine kinase domain (TKD) activation loop (~7%) ( 1 ). There were two patients with core binding factor (CBF) translocations (one RUNX-RUNX1T1 and one CBFB-MYH11) and FLT3-ITD mutations. Netw. SORAML, a randomized placebo-controlled trial evaluated the efficacy and tolerability of 3+7 induction-consolidation with or without sorafenib in patients 60 years with newly diagnosed AML, irrespective of a FLT3mut (only 34% had FLT3mut). N. Engl. The MORPHO phase III placebo-controlled trial evaluating post-transplant maintenance with gilteritinib in FLT3mut AML recently completed accrual and results are eagerly awaited (NCT02997202). Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. T.C. Blood 132, 3944 (2018). FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. contracts here. The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. 2A). All eligible intermediate or high-risk patients (defined as patients with FLT3-ITDmut AR>0.50 irrespective of NPM1mut status, or FLT3-ITDmut AR<0.50 without NPM1mut) are equivocally recommended to proceed to ASCT in CR1 followed by post-ASCT FLT3i maintenance for at least 2 years (although we often continue indefinite FLT3i maintenance until long-term maintenance data becomes available). DiNardo, C. D. et al. Leukemia 26, 23532359 (2012). FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Cancer 125, 37553766 (2019). The combination continues to enroll. Overall survival (OS) was calculated from the date of the diagnosis of AML until death in all included patients. Log in with Facebook Log in with Google. 6,, - 9 In normal bone marrow, FLT3 expression is Br. No statistically significant differences were found (P=0.4) (Fig. Article Our results, alongside those of other non-significant reports, lead us to believe that FLT3-ITD length has neither prognostic value nor possible clinical application. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. 368, 20592074 (2013). Our treatment approach for FLT3mut AML in MD Anderson Cancer Center is as follows: in newly diagnosed patients who are eligible to receive intensive chemotherapy (Fig. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Google Scholar. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Article A detailed analysis of all patients showed ITD integrations in the JMD-B, amino acids 572 to 578, in six patients; the JMD-S, amino acids 579 to 592, in 42 patients; the JMD-Z, amino acids 593 to 603, in 43 patients; the HR, amino acids 604 to 609, in seven patients; the B1 of TKD1, amino acids 610 to 615, in one patient; the NBL, amino acids 616 to 623, in two patients; and the B2, amino acids 624 to 630, in one patient. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. These combinations appear to improve the efficacy over single agent gilteritinib and could be considered if there is expertise in using such an approach, For patients relapsing while on gilteritinib or soon after gilteritinib based therapy a combination of azacitidine with sorafenib or azacitinde with venetoclax or gemtuzumab based approaches may be considered as salvage options (with clinical trials being clearly the best option if available). Correspondence to Minetto and colleagues retrospectively evaluated the efficacy of fludarabine, high-dose cytarabine, and idarubicin (FAI) in 149 newly diagnosed FLT3-ITDmut and/or NPM1mut AML (only FLT3-ITDmut=29; FLT3-ITDmut NPM1mut=59, only NPM1mut=61). Internet Explorer). 1B) we add a second generation FLT3i to the intensive induction backbone of cladribine or fludarabine with cytarabine and idarubicin (CLIA or FIA, respectively) as published previously by our group61,62. The Programa Espaol de Tratamientos en Hematologa (PETHEMA) AML epidemiologic registry (NCT02607059) includes patients diagnosed with AML, regardless of the treatment administered. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Ninety-eight patients had ITD insertion sites in the JMD domain (JM-B, n=6; JM-S, n=42; JM-Z, n=43; and hinge region (HR), n=7), four patients had ITD insertion sites in the TKD1 domain (beta1-sheet, n=1; beta2-sheet, n=1; and nucleotide binding loop (NBL), n=2) and four patients had ITD insertion sites in the extracellular domain (ED) (Fig. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). Therefore, in patients not eligible for intensive chemotherapy at MDACC, we prefer a combination of HMA with venetoclax and FLT3i (gilteritinib) over an HMA with venetoclax doublet (Fig. A Conventional approach. This is in line with the preclinical data49 and molecular profiling of pre- and post-treatment samples66 identifying FLT3-ITDmut as a putative mechanism of resistance to venetoclax based therapies67, suggesting that FLT3-ITDmut patients may need a FLT3i incorporated into the HMA with venetoclax therapy either in a triplet or sequential approach to improve OS. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. The CRc rates with quizartinib were similar to prior studies (48.2%), and 32% patients on the quizartinib arm underwent ASCT compared with 11% with salvage chemotherapy. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. J. Hematol. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. 94, 984991 (2019). Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. Similarly, a stratified analysis of FLT3-ITD length on the basis of 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<39bp, n=31 and ITD39bp, n=68; intermediate-II group, ITD<39bp, n=5 and ITD39bp, n=10; and adverse group, ITD<39bp, n=2 and ITD39bp, n=7). Res. PubMedGoogle Scholar. J. Haematol. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. CAS Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. CAS In summary, in our population of 161 intensively treated FLT3-ITD AML patients, we did not validate any of the previously published recurrent thresholds of ITD length obtained from smaller series.